Submissions for variant NM_000352.6(ABCC8):c.3545G>A (p.Arg1182Gln)

dbSNP: rs193922400

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029257	SCV000051903	likely pathogenic	Neonatal diabetes mellitus	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Invitae	RCV001388602	SCV001589658	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1182 of the ABCC8 protein (p.Arg1182Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant neonatal diabetes mellitus (PMID: 16885549, 17446535, 22749773, 24622368). This variant is also known as Arg1183Gln. ClinVar contains an entry for this variant (Variation ID: 35611). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC8 protein function. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 22451668). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001388602	SCV002023927	likely pathogenic	not provided	2020-03-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000193953	SCV002070463	pathogenic	Diabetes mellitus, transient neonatal, 2	2019-06-17	no assertion criteria provided	clinical testing	DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.3545G>A, in exon 28 that results in an amino acid change, p.Arg1182Gln. This sequence change has been previously described in patients with transient neonatal diabetes, in both the de novo (PMID: 17389331) and familial state (PMIDs: 16885549, 22749773). It was identified in a father of one patient who presented with type 2 diabetes occurring later in life which was treated with diet alone (PMID: 16885549). Another missense variant affecting the same amino acid residue, p.Arg1182Trp, has also been described in patients with neonatal diabetes presenting with severe hyperglycemia (Flanagan et al., 2007). This sequence change has not been described in the population databases such as ExAC and gnomAD (dbSNP rs193922400). The p.Arg1182Gln change affects a highly conserved amino acid residue located in a functional domain of the ABCC8 protein that is known to be functional.